A promising approach to cancer chemotherapy has been the use of molecules which can selectively interact with the functional site of a protein in a tumor cell in such a way that the activity of the protein is modified or eliminated. The protein so attacked could be a cytoplasmic enzyme or a membrane-associated protein. Great selectivity is necessary in such reagents since differences between the various enzymes and structural proteins of normal and cancerous cells may be slight. If other than a purely empirical application of this type of chemotherapy is to be made, methods which lead to a workable understanding of the chemical and physical forces which control a given protein-small molecule interaction are needed. Nuclear magnetic resonance spectroscopy offers many advantages in studies of protein- small molecule interactions and in elucidating the nature of cell membranes. Experiments with carbon-13 and fluorine-19 nuclei are especially useful since these nuclei can often be incorporated fairly simply into the structure to be studied and nuclear signals from these species can be observed without interference from the hydrogen atoms of the structure. We propose to continue studies underway by (1) preparing fluorine or carbon-labelled reagents for the tagging of interaction sites on proteins (2) examining the chemical shift and relaxation behaviour of nuclei in proteins modified with the reagents in order to define the conformational mobility of the probe nuclei, (3) developing double resonance techniques for use in ascertaining amino acid-probe interactions and (4) studying the effect of environmental parameters on these interactions. Since significant membrane changes accompany neoplasia these techniques will be applied to proteins involved in transport functions in bacterial and mammalian cells, in particular. Our long range goal is the development of chemical and instrumental techniques that will make nmr studies of protein-small molecule interactions facile and revealing. Ultimately drug molecules with greater specificity can be designed to take advantage of the structural features so defined, resulting in more selective and efficient chemotherapeutic agents for the control of cancer.